Microglia and Complement in Alzheimer's Disease with Cerebral Amyloid Angiopathy.

摘要

Alzheimer's disease (AD) is the most common form of dementia and completely lacks any viable, long-term therapeutic intervention. This is partly due to an incomplete understanding of AD etiology and the possible confounding factors associated with its genotypic and phenotypic heterogeneity. Cerebral amyloid angiopathy (CAA) is a common, yet frequently overlooked, pathology associated with AD. A pathological hallmark of AD consists of extracellular amyloid-beta (Aβ) deposits, while CAA manifests with deposition Aβ within the smooth muscle layer of cerebral arteries and arterioles. The role of Aβ in AD and CAA pathophysiology has long been controversial. Although it may have toxic effects at super-physiological levels, Aβ load does not necessarily correlate with cognitive demise in humans. Described in this dissertation is an alternative viewpoint that the toxicity afforded by Aβ could be due, in part, to complement system activation--a potent inflammatory cascade, which left unchecked can cause robust cell death. We have found increased levels of the lytic Membrane Attack Complex (MAC) on vessels harboring CAA compared to vessels from AD patients without CAA and pathological controls. Additionally, the same vessels also show trending decreases in the endogenous MAC inhibitor, CD59. We believe the differential complement phenotype on vessels could be due to an upstream shift in how Aβ is trafficked to the blood stream for clearance. We found more Aβ bound to the microglial CD11b receptor through complement C3b in CAA patients compared to AD and control subjects. Additionally, 75% of CAA patients in this cohort harbor the CAA risk haplotype rs6656401 at the CR1 gene, which seems to modify the localization of CR1 molecules from the membrane to endosomal structures. Because CR1 functions on the cell surface to block C3b generation, mislocalization to intracellular compartments may explain the increased C3b found in subjects with CAA. Increased availability of parenchymal C3b to bind Aβ may explain the robust staining of MAC on CAA blood vessels. These observations in human postmortem brain help explain the high frequency of microbleeds and hemorrhage associated with CAA and may offer a novel therapeutic target to reduce these life-threatening events.